Sustained-release preparation

Abstract

According to a first embodiment, there is provided a sustained-release preparation comprising a water-insoluble or slightly water-soluble polyvalent metal salt of a water-soluble physiologically active substance which is not an endothelin antagonist, and a biodegradable polymer. The sustained-release preparation of the first embodiment is highly efficient in incorporating the water-soluble physiologically active substance and suppresses the initial burst of the water-soluble physiologically active substance. The sustained-release preparation of the present invention is capable of releasing the water-soluble physiologically active substance while retaining its bioactivity after administration in vivo. Furthermore, the water-soluble physiologically active substance in the sustained-release preparation is kept stable for a long period of time, with little loss of bioactivity. According to a second embodiment, there is provided a sustained-release preparation comprising an anti-endothelin substance and a biodegradable polymer. The sustained-release preparation of the present invention sustainedly releases an anti-endothelin substance, serving well in the treatment of endothelin-associated diseases.

1 . A sustained-release preparation which comprises 
 (a) a water-insoluble or slightly water-soluble polyvalent metal salt of a water soluble peptide type of physiologically active substance except for an endothelin antagonist and    (b) a biodegradable polymer.    
     
     
         2 . A preparation of  claim 1 , wherein the physiologically active substance is a water soluble peptide or a derivative thereof.  
     
     
         3 . A preparation of  claim 2 , wherein the peptide is a hormone, cytokine, hematopoietic factor, growth factor, enzyme, soluble or solubilized receptor, antibody, antigen containing peptide, blood coagulation factor or adhesion molecule.  
     
     
         4 . A preparation of  claim 2 , wherein the peptide is a hormone.  
     
     
         5 . A preparation of  claim 4 , wherein the hormone is a growth hormone.  
     
     
         6 . A preparation of  claim 4 , wherein the hormone is an insulin.  
     
     
         7 . A preparation of  claim 2 , wherein the peptide is a cytokine.  
     
     
         8 . A preparation of  claim 7 , wherein the cytokine is an interferon.  
     
     
         9 . A preparation of  claim 2 , wherein the peptide is a growth factor.  
     
     
         10 . A preparation of  claim 1 , wherein the polyvalent metal salt is a transition metal salt.  
     
     
         11 . A preparation of  claim 1 , wherein the polyvalent metal salt is a zinc salt.  
     
     
         12 . A preparation of  claim 1 , wherein the solubility of the polyvalent metal salt to water is about 0 to about 0.1% (w/w) at 20° C.  
     
     
         13 . A preparation of  claim 1 , wherein the solubility of the polyvalent metal salt to water is about 0 to about 0.1% (w/w).  
     
     
         14 . A preparation of  claim 1 , which contains about 0.1 to about 50% (w/w) of the polyvalent metal salt.  
     
     
         15 . A preparation of  claim 1 , which contains about 1 to about 30% (w/w) of the polyvalent metal salt.  
     
     
         16 . A preparation of  claim 1 , wherein the biodegradable polymer is an aliphatic polyester.  
     
     
         17 . A preparation of  claim 16 , wherein the aliphatic polyester is a polymer of lactic acid and glycolic acid.  
     
     
         18 . A preparation of  claim 17 , wherein the composition ratio of lactic acid and glycolic acid is 100/0 to about 40/60 (mole %).  
     
     
         19 . A preparation of  claim 18 , wherein the composition ratio is about 90/10 to about 45/55 (mole %).  
     
     
         20 . A preparation of  claim 17 , wherein the weight-average molecular weight of the polymer is about 3,000 to about 20,000.  
     
     
         21 . A preparation of  claim 17 , wherein the weight-average molecular weight of the polymer is about 3,000 to about 14,000.  
     
     
         22 . A preparation of  claim 16 , wherein the alihatic polyester is a homopolymer of lactic acid.  
     
     
         23 . A preparation of  claim 22 , wherein the weight-average moecular weight of the homopolymer is about 3,000 to about 20,000.  
     
     
         24 . A preparation of  claim 22 , wherein the weight-average molecular weight of the homopolymer is about 3,000 to about 14,000.  
     
     
         25 . A preparation of  claim 1 , wherein the preparation is a microcapsule.  
     
     
         26 . A preparation of  claim 25 , wherein the microcapsule is for injection.  
     
     
         27 . A preparation of  claim 1 , which is an injectable one,  
     
     
         28 . Use of a water-insoluble or slightly water-soluble polyvalent metal salt of a water-soluble peptide type of physiologically active substance except for an endothelin antagonist and a biodegradable polymer for the production of a sustained-release preparation.  
     
     
         29 . A method of producing a sustained-release preparation, which comprises dispersing a water-insoluble or slightly water-soluble polyvalent metal salt of a water-soluble peptidfe type of physiologically active substance except for an endothelin antagonist in an oil phase containing a biodegradable polymer to make a solid-in-oil emulsion, adding the solid-in-oil emulsion to a water phase to make a solid-in-oil-in-water emulsion, and then in-water drying the soild-in-oil-in-water emulsion.  
     
     
         30 . A sustained-release preparation which comprises an anti-endothelin substance and a biodegradable polymer.  
     
     
         31 . The sustained-release preparation according to  claim 30 , wherein the anti-endothelin substance is an endothelin antagonist.  
     
     
         32 . The sustained-release preparation according to  claim 31 , wherein the endothelin antagonist is a peptide.  
     
     
         33 . The sustained-release preparation according to  claim 31 , wherein the endothelin antagonist is a peptide of the general formula:  
       
         
           
           
               
               
           
         
       
       wherein X and Y independently represent an α-amino acid residue; A represents a D-acidic-α-amino acid residue; B represents a neutral-α-amino acid residue; C represents an L-α-amino acid residue; E represents a D-α-amino acid residue having an aromatic cyclic group, or an ester thereof, or a salt thereof.  
     
     
         34 . The sustained-release preparation according to  claim 33 , wherein the peptide is a compound of the formula cyclo[-D-Asp-Asp(R1′)-Asp-D-Thg(2)-Leu-D-Trp-] wherein Asp represents aspartic acid; Asp(R1′) represents aspartic acid β-4-phenylpiperazinamide; Thg(2) represents 2-thienylglycine; Leu represents leucine; and Trp represents tryptophan.  
     
     
         35 . The sustained-release preparation according to  claim 33 , wherein A is a D-acidic-α-amino acid residue which is esterified with an alkyl group.  
     
     
         36 . The sustained-release preparation according to  claim 33 , wherein Y is a L-acidic-α-amino acid residue.  
     
     
         37 . The sustained-release preparation according to  claim 33 , wherein Y is a L-acidic-α-amino acid residue which is esterified with an alkyl group.  
     
     
         38 . The sustained-release preparation according to  claim 33 , wherein the peptide is a compound of the formula, cyclo-[-D-Asp(OC 2 H 5 )-Asp(R1′)-Asp(OC 2 H 5 )-D-Thg(2)-Leu-D-Trp-] wherein Asp represents aspartic acid; Asp(R1′) represents aspartic acid β-4-phenylpiperazinamide; Thg(2) represents 2-thienylglycine; Leu represents leucine; and Trp represents tryptophan.  
     
     
         39 . The sustained-release preparation according to  claim 33 , wherein the salt is a polyvalent metal salt.  
     
     
         40 . The sustained-release preparation according to  claim 39 , wherein the polyvalent metal salt is a zinc salt.  
     
     
         41 . The sustained-release preparation according to  claim 30 , wherein the biodegradable polymer is an aliphatic polyester.  
     
     
         42 . The sustained-release preparation according to  claim 41 , wherein the aliphatic polyester is a copolymer of glycolic acid and lactic acid.  
     
     
         43 . The sustained-release preparation according to  claim 42 , wherein the copolymer has a weight-average molecular weight of about 2,000 to 50,000, as determined by Gel Permeation Chromatography.  
     
     
         44 . The sustained-release preparation according to  claim 42 , wherein the copolymer has a dispersity of about 0.2 to 4.0.  
     
     
         45 . The sustained-release preparation according to  claim 30 , which further comprises an organic basic substance.  
     
     
         46 . The sustained-release preparation according to  claim 30 , which further comprises a water-soluble polyvalent metal salt.  
     
     
         47 . A method for treatment of diseases caused by endothelin comprising administering to a patient in need thereof an effective amount of the sustained-release preparation according to  claim 30 .  
     
     
         48 . The method according to  claim 47 , wherein the diseases are chronic diseases.  
     
     
         49 . The method according to  claim 48 , wherein the chronic diseases are chronic complications in diabetes mellitus.  
     
     
         50 . The method according to  claim 49 , wherein the chronic complications are diabetic nephropathy.  
     
     
         51 . An injectable preparation which comprises the sustained-release preparation as claimed in  claim 30 .  
     
     
         52 . A peptide of the general formula:  
       
         
           
           
               
               
           
         
       
       wherein X and Y independently represent an α-amino acid residue; A′ represents a D-acidic-α-amino acid residue which is esterified with an alkyl group; B represents a neutral-α-amino acid residue; C represents an L-α-amino acid residue; E represents a D-α-amino acid residue having an aromatic cyclic group, or a salt thereof.  
     
     
         53 . The peptide according to  claim 52 , wherein X is an L-isomer.  
     
     
         54 . The peptide according to  claim 52 , wherein Y is an L-isomer.  
     
     
         55 . The peptide according to  claim 52 , wherein A′ is D-glutamic acid or D-aspartic acid which is esterified with an alkyl group.  
     
     
         56 . The peptide according to  claim 52 , wherein B is an D-isomer.  
     
     
         57 . The peptide according to  claim 52 , wherein B is selected from the group consisting of D-leucine, D-alloisoleucine, D-tertiary leucine, D-gamma methyl leucine, D-phenylglycine, D-2-thienylglycine, D-3-thienylglycine, D-2-cyclopentylglycine, D-phenylalanine, D-2-thienylalanine, D-valine, D-2-furylglycine and D-3-furylglycine residues.  
     
     
         58 . The peptide according to  claim 52 , wherein C is selected from the group consisting of L-leucine, L-phenylalanine and L-tryptophan residues.  
     
     
         59 . The peptide according to  claim 52 , wherein E is selected from the group consisting of D-tryptophan or derivatives thereof, D-1-naphthylalanine, D-2-naphthylalanine, D-benzothienylalanine, D-4-bisphenylalanine and D-pentamethyl phenylalanine residues.  
     
     
         60 . The peptide according to  claim 52 , wherein Y is an α-amino acid residue having a carboxyl group which is esterified with an alkyl group.  
     
     
         61 . A peptide of the formula: cyclo-[-D-Asp(OC 2 H 5 )-Asp (R1′)-Asp(OC 2 H 5 )-D-Thg(2)-Leu-D-Trp-], wherein Asp represents aspartic acid; Asp (R1′) represents aspartic acid β-4-phenylpiperazinamide; Thg(2) represents 2-thienylglycine; Leu represents leucine; and Trp represents tryptophan, or a salt thereof.  
     
     
         62 . A zinc salt of a peptide represented by the general formula:  
       
         
           
           
               
               
           
         
       
       wherein X and Y independently represent an α-amino acid residue; A represents a D-acidic-α-amino acid residue; B represents a neutral-α-amino acid residue; C represents an L-α-amino acid residue; and E represents a D-α-amino acid residue having an aromatic cyclic group.